ATF3 deficiency impairs the proliferative–secretory phase transition and decidualization in RIF patients

Abstract

Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma and is required to establish and support pregnancy. Dysregulated decidualization has been reported to be a critical cause of recurrent implantation failure (RIF). In this study, we found that Activating transcription factor 3 (ATF3) expression was significantly downregulated in the endometrium of RIF patients. Knockdown of ATF3 in human endometrium stromal cells (hESCs) hampers decidualization, while overexpression could trigger the expression of decidual marker genes, and ameliorate the decidualization of hESCs from RIF patients. Mechanistically, ATF3 promotes decidualization by upregulating FOXO1 via suppressing miR-135b expression. In addition, the endometrium of RIF patients was hyperproliferative, while overexpression of ATF3 inhibited the proliferation of hESCs through CDKN1A. These data demonstrate the critical roles of endometrial ATF3 in regulating decidualization and proliferation, and dysregulation of ATF3 in the endometrium may be a novel cause of RIF and therefore represent a potential therapeutic target for RIF.

Identification of Key Endometrial MicroRNAs and Their Target Genes Associated With Pathogenesis of Recurrent Implantation Failure by Integrated Bioinformatics Analysis

“…Hsa-miR-135b-5p in serum exosome promotes proliferation and migration of VSMCs ( Zhang et al, 2020 ) and could be a prognostic biomarker in breast cancer and lupus nephritis ( Bao et al, 2019 ; Garcia-Vives et al, 2020 ). Suppression of hsa-miR-135b-5p promotes the decidualization of the endometrial stroma and ameliorates the decidualization of human endometrial stromal cells (hESCs) from RIF patients ( Wang et al, 2021 ). Interestingly, has-miR-135b-5p was significantly upregulated in the RIF samples in our study, indicating a suppressed decidualization which finally leads to the RIF.…”

Expression, Regulation, and Functions of the Galectin-16 Gene in Human Cells and Tissues

“…They are subunits of activating protein 1 (AP-1) TFs, which function as homodimers or heterodimers in association with other members of JUN, FOS, ATF, and MAF protein families [ 44 ]. JUNB was reported to be directly involved in processes of trophoblastic cell syncytialization [ 45 , 46 ], while upregulation of ATF3 was associated with cellular stress responses [ 41 , 47 , 48 ], decidualization [ 47 ], and preeclampsia [ 49 ]. In comparison, SMAD9 is activated by bone morphogenic proteins (BMPs), a subfamily of the transforming growth factor-β (TGF-β) family [ 40 , 50 ].…”

Liver Ischemia and Reperfusion Induce Periportal Expression of Necroptosis Executor pMLKL Which Is Associated With Early Allograft Dysfunction After Transplantation

“…The related clinical data belonging to the images was unknown at that time. After color deconvolution, the pixel intensity of cytoplasmic pMLKL staining, visualized by DAB, was automatically determined using the plugin IHC Profiler ( 36 – 38 ) and ImageJ software, in which high-positive, moderate-positive, low-positive, and negative zones were calculated. The threshold assignment was encoded in the plugin and performed automatically ( 38 ).…”

“…The threshold assignment was encoded in the plugin and performed automatically ( 38 ). We calculated the H-Score [scale 0 to 300, exemplified images were shown in Figure S1C )] for each image based on the generated products of the percentage contribution of positive zones and the intensity of labeling (0=negative; 1 = weak positive; 2 = moderate positive; 3 = high positive) using the following equation ( 36 , 37 , 39 ):…”